Effect of SMP-500, a novel ACAT inhibitor,on hepatic cholesterol disposition in rats |
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Authors: | Ioriya Katsuhisa Nishimura Takeshi Ohashi Naohito |
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Affiliation: | (1) Research Division, Sumitomo Pharmaceuticals Co., Ltd., 1-98, Kasugade Naka 3-chome, Konohana-ku, 554-0022 Osaka, Japan |
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Abstract: | The effects of SMP-500, a novel ACAT inhibitor, on serum lipid levels, hepatic lipid secretion rate, and hepatic lipid disposition
in rats were studied to clarify its lipid-lowering action. SMP-500 reduced the serum cholesterol level in a dose-dependent
manner in rats fed a hypercholesterolemic diet. SMP-500 also reduced hepatic free cholesterol content in addition to hepatic
total and esterified cholesterol contents. Biliary concentrations of cholesterol and bile acid were increased by SMP-500;
however, the bile flow and lithogenic index were not affected. SMP-500 increased cholesterol 7α-hydroxylase mRNA level. Therefore,
it is suggested that the increase in concentrations of cholesterol and bile acid in bile is due to both the increase of bile
acid production through the increase of cholesterol 7α-hydroxylase and the decrease of hepatic free cholesterol content. An
inhibitory effect of SMP-500 both on the cholesterol secretion and on the TG secretion from liver was observed. SMP-500 reduced
the serum TG level in sucrose-fed rats. From these results, one may hypothesize that the suppression of hepatic VLDL secretion
probably plays an important role on both cholesterol- and TG-lowering effects of SMP-500. |
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